EP3565556A1 - Dérivés de morphinane et compositions les comprenant pour traiter des troubles auto-immuns, inflammatoires ou infectieux - Google Patents

Dérivés de morphinane et compositions les comprenant pour traiter des troubles auto-immuns, inflammatoires ou infectieux

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Publication number
EP3565556A1
EP3565556A1 EP17889549.6A EP17889549A EP3565556A1 EP 3565556 A1 EP3565556 A1 EP 3565556A1 EP 17889549 A EP17889549 A EP 17889549A EP 3565556 A1 EP3565556 A1 EP 3565556A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
phenyl
formula
disease
Prior art date
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EP17889549.6A
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German (de)
English (en)
Other versions
EP3565556A4 (fr
Inventor
Syaulan S. YANG
Kuang-Yuan Lee
Edwin Sc Wu
Ming-Yu Hsiao
Hsiao-Chun Wang
Meng-Hsien Liu
Peter Js Chiu
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TaiwanJ Pharmaceuticals Co Ltd
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TaiwanJ Pharmaceuticals Co Ltd
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Publication of EP3565556A1 publication Critical patent/EP3565556A1/fr
Publication of EP3565556A4 publication Critical patent/EP3565556A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure in general relates to the field of morphinans, more particularly to the derivatives of morphinans, and their use as toll-like receptor 4 (TLR-4) antagonists in the treatment of diseases and/or disorders resulted from the activation of TLR- 4.
  • TLR-4 toll-like receptor 4
  • TLRs toll-like receptors
  • TLR-4 Toll-like receptor 4
  • TLR4 is a cell surface, type 1 transmembrane protein, present in macrophages such as the Kupffer cells of the liver.
  • TLR4 plays an important role in recognizing and mediating macrophage activation and pro-inflammatory cytokine release along the immunological cascade.
  • Activation of a TLR by its relevant ligand rapidly ignites a complex intracellular signaling cascade that ultimately results in upregulation of inflammatory genes and production of pro-inflammatory cytokines, interferons and recruitment of myeloid cells. It also stimulates expression, upon antigen presenting cells, of co-stimulatory molecules, required to induce, an adaptive imfflune response,
  • TLR response is critical for survival and defense against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental. Such 'unhelpful TLR responses' could result in various autoimmune diseases and inflammatory diseases.
  • TLR -4 antagonists in the treatment of diseases and/or disorders resulted from the activation of TL -4 is needed.
  • the present disclosure is based on unexpected discovery that certai mo rphinan derivatives are potent antagonists of TLR- , thus are useful as lead compounds for the development of medicaments for the treatment of diseases and/or disorders mediated by TLR-4, such as autoimmune diseases, ;, inflammatory diseases and/or infectious diseases,
  • one aspect of the present, disclosure is to provide; a novel compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof :
  • R is EI, C 1-20 alkyl, aryl, -[CH ⁇ -C i, or -(CH 2 N iRii
  • A is cycloalkyl, heteroeycloalkyl, phenyl, aryl or heteroaryl;
  • Ri and R 2 are independently H, C 1-20 alkyl, C 1 -2 o alkoxy, phenyl, or aryl;
  • X 1 is nil, S or O
  • each C 1-2 o alkyl and C 1-20 alkoxy is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkoxy, and phenyl;
  • each cycolalkyl, heterocycloalkyl, phenyl, aryl and heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, C 1-2 o alkyl, hydroxyl, alkoxy, haloalkyl, haloalkoxy, nitro, -NR 3 R 4 , -(CO)Ri and -(CO)OR 1 ; and
  • R 3 and R 4 are independently H, C 1-2 o alkyl, phenyl, aryl, -(CO)R 1 or -(CO)OR 1 .
  • the compound of formula (I) can be the compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, C 1-20 alkyl, aryl, -(CH 2 ) n -ORi, or -(CH 2 ) n -NR 1 R 2 ;
  • X I is nil, S or O
  • X 2 is N or C
  • Y is N, C or O
  • n is an integral between 1 to 10;
  • Z 2 are independently H, halogen, C 1-20 alkyl, -NR 1 R 2 , nitro, -OR 1; -
  • Ri and R 2 are independently H, halogen, C 1-20 alkyl, C 1-20 alkoxy, phenyl, or aryl; each C 1-2 o alkyl and C 1-2 o alkoxy is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkoxy, and phenyl;
  • each phenyl and aryl is optionally substituted with at least one substituent selected from the group consisting of halogen, C 1-20 alkyl, hydroxyl, alkoxy, haloalkoxy, nitro, -NR 3 R 4 , -(CO)Ri and -(CO)OR i ; and
  • R 3 and R4 are independently H, C 1-2 o alkyl, phenyl, aryl, -(CO)Ri or -(CO)OR 1 .
  • the compound of Formula (I) can be the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, or C 1-2 o alkyl
  • X is nil or -S0 2 -;
  • Zi and Z 2 are independently H, -NRiR 2 hinder nitro, -OR, -R 5 , or -NH(CO)R 5 ;
  • Ri and R 2 are independently H, halogen, C 1-20 alkyl, C 1-20 alkoxy, phenyl, or aryl;
  • R5 is H, halogen, C 1 -2 o alkyl or C 1 -2 o alkoxy optionally substituted with halogen or phenyl.
  • R is methyl or H
  • X is nil
  • Yi is C
  • Z is nitro or amino
  • Z 2 is H or amino
  • R is H, X is nil, Yi is C, Zi is amino, and Z 2 is R5, R5 is fluorine, methyl, or trifluoromethyl.
  • R is H, X is nil, Yi is C, and Zi is - NRiR 2 , each of Ri, R 2 is H or isopropyl, and Z 2 is H.
  • R is methyl, X is nil, Yi is C, and Zi is - NH(CO)R 5 , Z 2 is H, and R 5 is ethoxy.
  • R is methyl, X is nil, Yi is C, and Zi is -NH(CO)R 5 , Z 2 is H, and R 5 is propyl substituted with a phenyl.
  • R is H
  • X is -S0 2 -
  • Yi is C
  • Zi is - NH(CO)R 5
  • Z 2 is H
  • R 5 is methyl
  • R is H
  • X is -S0 2 -
  • Yi is C
  • Zi is - NRiR 2
  • each of R ls R 2 is H
  • Z 2 is H.
  • R is methyl
  • X is -S0 2 -
  • Yi is C
  • Zi is nitro
  • Z 2 is H.
  • R is methyl
  • X is -S0 2 -
  • Y 1 is C
  • Zi is amino
  • Z 2 is H.
  • R is H
  • X is nil
  • Yi is N
  • Zi is nitro
  • Z 2 is H.
  • R is H
  • X is nil
  • Yi is N
  • Zi is amino
  • Z 2 is H.
  • the compound of Formula (I) can be the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, or Ci_ 20 alkyl
  • Xi is nil, S or O
  • B is phenyl or heterocycloalkyl optionally substituted with halogen, Ci -2 o alkyl, alkoxy, haloalkoxy, amino or nitro.
  • R is methyl
  • Xi is nil
  • B is a 6-membered hetero eye lo alkyl .
  • R is methyl
  • Xi is S
  • B is phenyl
  • a further aspect of the present disclosure is to provide a pharmaceutical composition for the treatment of a subject having or suspected of having a disease and/or disorder mediated by TLR-4.
  • the disease and/or disorder mediated by TLR-4 may be an autoimmune disease, an inflammatory disease or an infectious disease.
  • the pharmacological composition comprises a therapeutically effective amount of the compound of Formula (I) to (IV); and a pharmaceutically acceptable carrier.
  • the compound of Formula (I) to (IV) is present at a level of about 0.1% to 99% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the compound of Formula (I) to (IV) is present at a level of at least 1% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the compound of Formula (I) to (IV) is present at a level of at least 5% by weight, based on the total weight of the pharmaceutical composition. In still other embodiments, the compound of Formula (I) to (IV) is present at a level of at least 10% by weight, based on the total weight of the pharmaceutical composition. In still yet other embodiments, the compound of Formula (I) to (IV) is present at a level of at least 25% by weight, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition further comprises an immunosuppressant, an anti-inflammation agent or anti-infectious agent.
  • the immunosuppressant may be a corticosteroid, a calcineurin inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, an Inosine monophosphate dehydrogenase (IMPDH) inhibitor, a therapeutic protein, or a monoclonal antibody.
  • the anti-inflammation agent may be a cyclooxygenase (COX) inhibitor, particularly a COX-2 inhibitor.
  • the anti- infectious agent may be an antibiotic that inhibits the growth of Gram-negative or Gram-positive bacteria.
  • the present disclosure also encompasses a method for the treatment of a subject having a disease and/or disorder mediated by the activation of TLR-4.
  • the method comprises the step of administering the present pharmaceutical composition to the subject, so as to ameliorate, mitigate and/or prevent the symptoms of the disease and/or disorder mediated by TLR-4.
  • the disease and/or disorder mediated by TLR-4 may be an autoimmune disease, an inflammatory disease or an infectious disease.
  • Examples of the autoimmune disease treatable by the present method include, but are not limited to, multiple sclerosis, psoriasis, systemic lupus erythemotosis (SLE), Type I diabetes mellitus, and Wegener's granulomatosis.
  • Examples of the inflammatory disease treatable by the present method include, but are not limited to, asthma, allergic rhinitis, acute and chronic liver diseases, atherosclerosis, cancer, Crohn's disease, hypersensitivity lung disease, irritable bowel syndrome (IBS), inflammatory dermatoses, Sjogren's syndrome, systemic inflammatory response syndrome (SIRS), and ulcerative colitis.
  • IBS irritable bowel syndrome
  • Sjogren's syndrome systemic inflammatory response syndrome
  • ulcerative colitis ulcerative colitis.
  • infectious disease treatable by the present method include, but are not limited to, bacterial, fungal and viral infections.
  • the method further includes the step of administering to the subject another agent that is known to improve the symptoms of the disease and/or disorder mediated by TLR-4, such as an immunosuppressant, an anti- inflammation agent, or an anti-infectious agent before, together with, or after the administration of the present pharmaceutical composition.
  • another agent that is known to improve the symptoms of the disease and/or disorder mediated by TLR-4, such as an immunosuppressant, an anti- inflammation agent, or an anti-infectious agent before, together with, or after the administration of the present pharmaceutical composition.
  • alkyl means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 ⁇ e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) carbon atoms.
  • Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl.”
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, 2-isopropyl-3-methyl butyl, pentyl, pentan-2-yl, hexyl, isohexyl, heptyl, heptan-2-yl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is substituted C 2 _ 10 alkyl. In some embodiments, cycloalkyl is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl").
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 _ 6 cycloalkyl").
  • C 5 _ 6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 6 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3_i o cycloalkyl.
  • the cycloalkyl group is substituted C 3 _ 10 cycloalkyl.
  • Hetero cycloalkyl refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon ("3-10 membered heterocycloalkyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • each instance of heterocycloalkyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents.
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • aryl means an aromatic ring or a partially aromatic ring system composed of carbon and hydrogen atoms.
  • An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include naphthyl, and phenyl.
  • each instance of an aryl group is independently optionally substituted, i. e. , unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl”) with one or more substituents.
  • the aryl group is a substituted phenyl.
  • heteroaryl means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g. , N, O or S).
  • a heteroaryl group is a 5- 10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6 membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • alkylaryl or "alkyl-aryl” means an alkyl moiety bound to an aryl moiety.
  • alkoxy means an -O-alkyl group.
  • alkoxy groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -0(CH 2 ) 3 CH 3 , -0(CH 2 ) 4 CH 3 , and -0(CH 2 ) 5 CH 3 .
  • lower alkoxy refers to -0-(lower alkyl), such as -OCH 3 and -OCH 2 CH 3 .
  • halogen and halo encompass fluoro, chloro, bromo, and iodo.
  • amino refers to a moiety of the formula: -N( ) 2 , wherein each instance of R is independently a substituent described herein, or two instances of R are connected to form substituted or unsubstituted heterocyclyl.
  • the amino is unsubstituted amino (i.e., -NH 2 ).
  • the amino is a substituted amino group, wherein at least one instance of R is not hydrogen.
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, -OH, -CHO, alkoxy, alkanoyloxy (e.g., -OAc), alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), aryl, aryloxy, halo, or haloalkyl (e.g., -CC1 3 , -CF 3 , -C(CF 3 ) 3 ).
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with one or more of: alkoxy, alkanoyloxy, alkyl, aryl, halo, haloalkyl, or hydro xyl.
  • one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
  • the phrase "optionally substituted alky, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl” has the same meaning as "optionally substituted alky, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.”
  • the present disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like.
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • diethyl ether diethyl ether
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound which is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R-x H 2 0, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • an effective amount of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition.
  • a therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition.
  • the term "effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C ⁇ alkyl) 4 " salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable carrier refers to a carrier, whether diluent or excipient, that is compatible with the other ingredients of a formulation and not deleterious to the recipient thereof.
  • administering a composition is defined to include an act of providing a compound or pharmaceutical composition of the present invention to the subject in need of treatment.
  • the compounds as described herein can have the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof: Formula: ' (j),
  • R may be: H, Ci. 20 alkyl, aryl, -( ⁇ 3 ⁇ 4) ⁇ -03 ⁇ 4, : or C3 ⁇ 4 3 ⁇ 4K? > in which n is an integral between. 1 to 10, and3 ⁇ 4 and.
  • R 2 may be independently H,
  • Ci.20 alkoxy phenyl, or aryl.
  • each Ci.3 ⁇ 4b alkyl . and Ci .20 alkoxy is substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkoxy, and phenyl,
  • R is O , alkyl, such as methyl, ethyl, propyl,, isopropyl, n-butyl, t-butyl, isbbutyl, 2-isoprOpyl-3-methyl butyl, pentyl, pentan-2-yl, hexyl, isohexyl, heptyl, heptan-2-yl, 4,4-dimethylp:entyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • R is methyl.
  • R is H.
  • Formul (I) may be nil, -SQ 2 - 3 or .
  • 3 ⁇ 4 may be nil,: S or ⁇ .
  • A may be selected from the group consisting of cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl, and each cycolalkyl, heterocycloalkyl, phenyl, aryl and heteroaryl may be optionally substituted with at least one substituent selected from the grou consisting of halogen, .20 alkyl, hydroxyl, alkoxy, haloalkoxy, haloalkyl, nitro, - NR3R 4 , -(CO)Ri and -(CO)ORi.
  • each R 3 and R 4 may be independently H, Ci. 20 alkyl. phenyl, aryl, ⁇ CO)Ri or -(CQ)ORi.
  • X is nil
  • A is phenyl optionally substituted with at least one substituent selected from the group consisting of halogen, Cr-20 alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, ⁇ NR 3 R 4 , -(CO)Ri and -(CO)ORi.
  • A is phenyl substituted with a. nitro. group.
  • A is phenyl substituted with -NR3R , where both R 3 and 4 are H or C1.20 alkyl.
  • A is phenyl substituted with a hitrp group and ah amino group.
  • A is phenyl substituted with - NR3R4, in which R 3 and R4 may be independently H, and -(CO)Ri, in which Ri is ethoxy.
  • A is phenyl substituted with -NR 3 R4, in which R 3 and R 4 may be independently H, and -(CO)ORi, in which Ri is propyl substituted with a phenyl group.
  • A is pyridinyl optionally substituted with at least one substituent selected from the group consisting of halogen, C 1-2 o alkyl, haloalkyl, nitro, and amino group.
  • X is -S0 2 -
  • A is a phenyl optionally substituted with at least one substituent selected from the group consisting of halogen, C 1-20 alkyl, hydroxyl, alkoxy, haloalkoxy, nitro, -NR3R4, -(CO)Ri and -(CO)ORi.
  • A is phenyl substituted with a nitro.
  • A is phenyl substituted with a -NR 3 R4, where both R3 and R4 are H.
  • X is , in which X 1 is S, and A is a phenyl.
  • X is , in which X 1 is O, and A is a phenyl.
  • X is , in which X 1 is nil, and A is a heterocycloalkyl, such as morpholinyl.
  • the compound of Formula (I) can be of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, C 1-20 alkyl, aryl, -( ⁇ 2 ) ⁇ -03 ⁇ 4, or -(CH 2 ) n -NR 1 R 2 ;
  • Xi is nil, S or O
  • X 2 is N or C
  • Y is N, C or O
  • n is an integral between 1 to 10;
  • Zi and Z 2 are independently H, C 1-2 o alkyl, amino, nitro, -ORi, -CR 1; -NH(CO)Ri, and -N(CO)OR i ;
  • R 2 are independently H, halogen, C 1-20 alkyl, C 1-20 alkoxy, phenyl, or aryl; each C 1-2 o alkyl and C 1-2 o alkoxy is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkoxy, and phenyl;
  • each phenyl and aryl is optionally substituted with at least one substituent selected from the group consisting of halogen, C 1-2 o alkyl, hydroxyl, alkoxy, haloalkoxy, nitro, -NR3R4, -(CO)Ri and -(CO)ORi; and
  • R 3 and R4 are independently H, C 1-20 alkyl, phenyl, aryl, -(CO)Ri or -(CO)ORi.
  • the compound of Formula (I) can be of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, or C 1-2 o alkyl
  • X is nil or -S0 2 -; Yi is C or N;
  • Z 1 andZ 2 are independently H, amino, nitro, -OR, -CR 5 , or -NH(CO)R5;
  • R5 is H, halogen, C 1 -20 alkyl or C 1 -20 alkoxy optionally substituted with halogen or phenyl.
  • R is H
  • X is nil
  • Z is amino
  • Z 2 is H.
  • R is methyl
  • X is S0 2
  • Z 2 is H
  • Z 2 is amino
  • the compound of Formula (I) can be of Formula (IV), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, and stereoisomer thereof:
  • R is independently H, or C 1-20 alkyl
  • Xi is nil, S or O
  • B is phenyl or heterocycloalkyl optionally substituted with halogen, C 1-2 o alkyl, alkoxy, haloalkoxy, amino or nitro.
  • R is methyl
  • Xi is S
  • B is phenyl
  • R is methyl
  • Xi is O
  • B is phenyl
  • Each compounds of the invention contain one or more stereocenters, thus can exist as racemic mixtures of enantiomers or mixtures of diastereomers.
  • This invention thus encompasses stereomerically pure forms of such compounds, as well as mixtures of those forms.
  • Stereoisomers may be asymmetrically synthesized or resolved using standard techniques such as crystallization, chromatography, and the use of a resolving agent.
  • One preferred way of separating enantiomers from a racemic mixture is by use of preparative high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the racemic may be separated into its enantiomers by reacting with an optically active form of a resolving agent in the presence of a solvent.
  • one of the two enantiomers is separated out as an insoluble salt with high yield and high optical purity, while the opposite enantiomer remains in the solution.
  • the present invention thus further encompasses stereoisomeric mixtures of compounds disclosed herein. It also encompasses configurational isomers of compounds disclosed herein (e.g., cis and trans isomers, whether or not involving double bonds), either in admixture or in pure or substantially pure form.
  • compounds of the invention are the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, co-crystals, and stereoisomers.
  • compounds of the invention are the compounds of any one of Formulae (I) to (IV), and pharmaceutically acceptable salts, solvates, hydrates, co- crystals, and stereoisomers.
  • compounds of the invention are the compounds of any one of Formulae (I) to (IV), and pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) may suppress the NF- ⁇ induced secretion of secreted alkaline phosphatase (SEAP), as well as lipopolysaccharide (LPS) induced TNF-a release, both mechanisms are respectively linked to the activation of toll-like receptor 4 (TL -4). Accordingly, the compound of Formula (I) acts as an antagonist of TLR-4, thus may be useful as a lead compound for the development of a medicament suitable for the treatment of diseases and/or disorders mediated by TLR-4.
  • SEAP secreted alkaline phosphatase
  • LPS lipopolysaccharide
  • a compound as described herein e.g., a compound of Formula (I)
  • a suitable compound e.g., 4-bromonitrobenzene or 2-(phenoxymethyl) oxirane
  • R is H, Ci. 20 alkyl, aryl, -(CH 2 ) n -ORi, or -(CH 2 ) n -NRi 2 ;
  • A is cycloalkyl, heterocycloalkyl, phenyl, aryl or heteroaryl;
  • n is an integral between 1 to 10;
  • Ri and R 2 are independently H, C 1-2 o alkyl, C 1 -2 o alkoxy, phenyl, or aryl;
  • Xi is nil, S or O;
  • each C 1-2 o alkyl and C 1-20 alkoxy is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, alkoxy, and phenyl;
  • each cycolalkyl, heterocycloalkyl, phenyl, aryl and heteroaryl is optionally substituted with at least one substituent selected from the group consisting of H, halogen, hydroxyl, C ⁇ o alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, -NR 3 R 4 , -(CO)R 1 and -(CO)OR 1 ; and
  • R 3 and R 4 are independently H, C 1-2 o alkyl, phenyl, aryl, -(CO)R 1 or -(CO)OR 1 ;
  • a Lewis acid can be used as a reaction promotor, which is selected from a group consisting of lithium, sodium, magnesium, calcium, zinc, aluminum, boron, indium, scandium, ytterbium, cerium, silicon, tin, titanium, zirconium, vanadium, iron, and cobalt salts with the counter anion selected from a group consisting of fluoride, chloride, bromide, iodide, hydroxide, methoxide, ethoxide, isoproproxide, feri-butoxide, acetate, oxalate, acetylacetonate, nitrate, phosphate, sulfate, bisulfate, and sulfonate.
  • sodium ierf-butoxide is used as the reaction promoter.
  • the reaction e.g., the step of contacting
  • a hydrocarbon solvent comprises an acyclic, cyclic, or aromatic solvent selected from the group consisting of /?-hexane, cyclohexane, benzene, toluene, and xylene.
  • the reaction promotor described above is mixed with a phosphonium based ionic liquid having a formula of [PHR 3 ] + X " , in which R is an alkly, and X is a counter anion.
  • a phosphonium based ionic liquid having a formula of [PHR 3 ] + X " , in which R is an alkly, and X is a counter anion.
  • sodium feri-butoxide i.e., the reaction promoter
  • tri-tert- butylphosphonium tetrafluoroborate i.e., a phosphonium based ionic liquid
  • compounds of Formula (III) is prepared by reacting a morphinan of Formula (V) with a suitable aryl compound:
  • R is independently H, or C 1-2 o alkyl
  • X is nil or -S0 2 -;
  • Zi and Z 2 are independently H, C 1-2 o alkyl, -CR 5 , amino, nitro, or -NH(CO)R 5 ;
  • R5 is halogen, C 1 -2 o alkyl, or C 1-2 o alkoxy optionally substituted with halogen or phenyl.
  • an aryl compound having suitable substituent(s) may be reacted with the compound of Formula (V).
  • 4-bromonitobeneze is mixed with 3- methoxymorphinan (compound 1) in toluene, which contains sodium ierf-butoxide as the reaction promoter and tri-tert-butylphosphonium tetrafluoroborate as the phosphonium based ionic liquid, allow the reaction to proceed until a product (i.e., compound 2) is produced.
  • a product i.e., compound 2
  • compound 2 react with hydrogen bromide, thereby produces compound 3; or palladium/carbon under hydrogen gas to produce compound 6.
  • 3- methoxymorphinan (compound 1) is reacted with 5-bromo-2-nitroaniline or 4- nitrobenezesulfonyl chloride in a similar manner to produce compound 5 or compound 9. Additionally, compounds 3 and 9 may be further subject to hydrogenation to produce compounds 4 and 10, respectively.
  • compounds 21-22 23, 24, and 25 are produced, respectively.
  • 3-methoxymorphinan (compound 1) is reacted with HBr to produce compound 14, which is further reacted with N-acetylsulfonyl chloride to produce compound 15.
  • compound 16 is then produced.
  • compound 17 and 18 are produced, respectively.
  • compound 4 is reacted with acetone, acetic acid and NaHB(OAc) 3 to produce compound 19 and 20, respectively.
  • morphinan is used as the starting material in the described reaction, (that is, by first reacting with 4- bromonitobeneze, followed by hydrogenation) to produce compound 6, which may then respectively reacted with diisopropylethyl acetate (DIPEA) and 4-phenylbutanoic acid, to produce compounds 7 and 8.
  • DIPEA diisopropylethyl acetate
  • compounds of Formula (IV) is prepared by reacting a morphinan of Formula (V) with an ethylene oxide derivative of formula B .
  • R is independently H, or C 1-2 o alkyl
  • Xi is nil, S or O
  • B is phenyl or heterocycloalkyl optionally substituted with halogen, C 1 -2 o alkyl, alkoxy, haloalkoxy, amino or nitro.
  • Formula (IV) a compound of formula ⁇ — 1 having suitable substituent(s) is reacted with the compound of Formula (V).
  • 2-(phenoxymethyl)oxirane is reacted with 3-methoxymorphinan (compound 1) to produce compound 11.
  • 2- ((phenylthio)methyl)oxirane and 4-(oxiran-2-yl)methyl)morpholine are respectively reacted with 3-methoxymorphinan (compound 1) to produce compounds 12 and 13.
  • This invention encompasses pharmaceutical compositions for the treatment of a disease and/or a disorder mediated by TLR-4.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I) to (IV) of the present invention.
  • the compound of Formula (I) to (IV) is present at a level of about 0.1% to 99% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the compound of Formula (I) to (IV) is present at a level of at least 1% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the compound of Formula (I) to (IV) is present at a level of at least 5% by weight, based on the total weight of the pharmaceutical composition. In still other embodiments, the compound of Formula (I) to (IV) is present at a level of at least 10% by weight, based on the total weight of the pharmaceutical composition. In still yet other embodiments, the compound of Formula (I) to (IV) is present at a level of at least 25% by weight, based on the total weight of the pharmaceutical composition.
  • the disease and/or disorder mediated by TLR-4 may be an autoimmune disease, an inflammatory disease or an infectious disease.
  • the autoimmune disease treatable by the present pharmaceutical composition include, but are not limited to, multiple sclerosis, psoriasis, systemic lupus erythemotosis (SLE), Type I diabetes mellitus, and Wegener's granulomatosis.
  • Examples of the inflammatory disease treatable by the present pharmaceutical composition include, but are not limited to, asthma, allergic rhinitis, acute and chronic liver diseases, atherosclerosis, cancer, Crohn's disease, hypersensitivity lung disease, irritable bowel syndrome (IBS), inflammatory dermatoses, Sjogren's syndrome, systemic inflammatory response syndrome (SIRS), and ulcerative colitis.
  • Examples of the infectious disease treatable by the present pharmaceutical composition include, but are not limited to, bacterial, fungal and viral infections.
  • the pharmaceutical composition may further comprise an immunosuppressant, an anti-inflammatory agent or an anti-infectious agent.
  • the immunosuppressant that may be used with the present pharmaceutical composition is a corticosteroid, a calcineurin inhibitor, a mammalian target of rapamycin (mTO ) inhibitor, an Inosine monophosphate dehydrogenase (IMPDH) inhibitor, a therapeutic protein, or a monoclonal antibody.
  • corticosteroid suitable as an immunosuppressant include, but are not limited to, prednisone, budesonide, and prednisolone.
  • Examples of calcineurin inhibitor suitable as an immunosuppressant include, but are not limited to, cyclosporine, and tacrolimus.
  • Examples of mTOR inhibitor suitable as an immunosuppressant include, but are not limited to, sirolimus, and everolimus.
  • Examples of IMDH inhibitor suitable as an immunosuppressant include, but are not limited to, azathioprine, leflunomide, and mycophenolate.
  • Examples of therapeutic protein suitable as an immunosuppressant include, but are not limited to, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and vedolizumab.
  • Examples of monoclonal antibody suitable as an immunosupressant include, but are not limited to, basiliximab, daclizumab, and muromonab.
  • the anti-inflammatory agent that may be used with the present pharmaceutical composition is a cyclooxygenase (COX) inhibitor, particularly a COX-2 inhibitor, such as Celebrex, Celecoxib, Rofecoxib, Valdecoxib, DuP-697, Etoricoxib, and Lumiracoxib.
  • COX cyclooxygenase
  • the anti- infectious agent suitable for use in the present pharmaceutical composition may be an anti-biotic that inhibits the growth of Gram-negative or Gram- positive bacteria.
  • antibiotic suitable as an anti-infectious agent include, but are not limited to, acumycin, ampicillin, amoxycillin, amphotericins, antimycins, anglomycin, avermectins, azithromycin, boromycin, carbomycins, carbapenem, ceftazidime, cethromycin, chloramphenicol, chalcomycin, ciprofloxacin, concanamycins, cirramycin, clarithromycin, colistin, cycloxacillin, daptomycin, desmethyl azithromycin, desertomycins, dihydropikromycin, dirithromycin, doxycycline, enramycin, erythromycin, flurithromycin, flumequin gentamycin, juvenimicins, kujimycins, lankamycins, l
  • compositions are single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra- arterial), or transdermal administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra- arterial
  • transdermal administration e.g., transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or nonaqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or
  • the formulation should suit the mode of administration.
  • oral administration requires enteric coatings to protect the compounds of this invention from degradation within the gastrointestinal tract.
  • a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action.
  • compounds may be administered in liposomal formulations, in order to protect them from degradative enzymes, facilitate transport in circulatory system, and effect delivery across cell membranes to intracellular sites.
  • poorly soluble compounds may be incorporated into liquid dosage forms (and dosage forms suitable for reconstitution) with the aid of solubilizing agents, emulsifiers and surfactants such as, but not limited to, cyclodextrins (e.g., a-cyclodextrin or p-cyclodextrin), and non-aqueous solvents, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide (DMSO), biocompatible oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof (e
  • composition, shape, and type of a dosage form will vary depending on its use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
  • compositions of the present invention suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by conventional methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets).
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: water; aqueous vehicles such as, but not limited to, sodium chloride solution, Ringer's solution, and Dextrose; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • water aqueous vehicles
  • water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl my
  • Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art.
  • Transdermal dosage forms include "reservoir type” or "matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention.
  • penetration enhancers may be used to assist in delivering active ingredients to the tissue.
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates may also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration- enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition
  • kits containing materials useful for the treatment or prophylaxis of a disease and/or disorder mediated by TL -4 in a subject.
  • the kit comprises a container comprising the compound of the present disclosure.
  • the kit is suitable for the treatment or prophylaxis of a disease and/or disorder mediated by TLR-4, such as autoimmune disease, inflammatory disease or infectious disease.
  • Suitable containers include, for example, bottles, vials, syringes, blister pack, and etc.
  • the container may be formed from a variety of materials such as glass, or plastic.
  • the contain may hold a compound of the present disclosure or a pharmaceutical formulation thereof, in an amount effective for the treatment or prophylaxis of the disease and/or disorder mediated by TLR-4, and may have a sterile access port, for example, the container may be an intravenous solution bag or a vail having a stopper pierceable by a hypodermic injection needle).
  • the kit may further comprise a label or package insert on or associated with the container. The label or package insert indicates that the composition is used for treating condition of choice.
  • the kit may further comprise a second container comprising a pharmaceutically acceptable buffer, such as a phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • the kit may further include directions for the administration of the compound of the present invention and, if present, the second formulation for treating or preventing the disease and/or disorder mediated by TLR-4.
  • the kit may further include directions for the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
  • the kits are suitable for the delivery of solid oral forms of a compound of the present disclosure, such a kit includes, for example, a number of unit dosages. Such kits include card having the dosages oriented in the order of their intended use.
  • kits are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.
  • an aid may be provided, for example, in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosage can be administered.
  • the Kit may include, at least, (a) a first container containing any of the present compound of Formula (I) to (IV); and optionally, (b) a second container containing a second therapeutic agent that is any of a known TL -4 antagonist, an anti- inflammatory agent, an anti-biotic, or an immunosuppressant; and (c) a legend associated with the kit for instructing a user how to use the kit.
  • the legend may be in a form of pamphlet, tape, CD, VCD or DVD.
  • the present invention encompasses a method for the treatment of a subject having a disease and/or a disorder mediated by TLR-4.
  • the method comprises the step of administering the present pharmaceutical composition, which comprises a therapeutically effective amount of any of the compound of Formula (I) to (IV) of the present disclosure, to the subject, so as to ameliorate, mitigate and/or prevent the symptoms of the disease and/or disorder mediated by TLR-4.
  • the disease and/or disorder mediated by TLR-4 may be an autoimmune disease, an inflammatory disease or an infectious disease.
  • the autoimmune disease treatable by the present method include, but are not limited to, multiple sclerosis, psoriasis, systemic lupus erythemotosis (SLE), Type I diabetes mellitus, and Wegener's granulomatosis.
  • the inflammatory disease treatable by the present method examples include, but are not limited to, asthma, allergic rhinitis, acute and chronic liver diseases, atherosclerosis, cancer, Crohn's disease, hypersensitivity lung disease, irritable bowel syndrome (IBS), inflammatory dermatoses, Sjogren's syndrome, systemic inflammatory response syndrome (SIRS), and ulcerative colitis.
  • infectious disease treatable by the present method examples include, but are not limited to, bacterial, fungal and viral infections.
  • the method further includes the step of administering to the subject, an immunosuppressant, an anti-inflammation agent, or an anti- infectious agent before, together with, or after the administration of the present pharmaceutical composition.
  • the immunosuppressant suitable for use in the present method may be a corticosteroid, a calcineurin inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, an Inosine monophosphate dehydrogenase (IMPDH) inhibitor, a therapeutic protein, or a monoclonal antibody.
  • mTOR mammalian target of rapamycin
  • IMPDH Inosine monophosphate dehydrogenase
  • therapeutic protein or a monoclonal antibody
  • Examples of corticosteroid suitable as an immunosuppressant include, but are not limited to, prednisone, budesonide, and prednisolone.
  • calcineurin inhibitor suitable as an immunosuppressant include, but are not limited to, cyclosporine, and tacrolimus.
  • Examples of mTOR inhibitor suitable as an immunosuppressant include, but are not limited to, sirolimus, and everolimus.
  • Examples of IMDH inhibitor suitable as an immunosuppressant include, but are not limited to, azathioprine, leflunomide, and mycophenolate.
  • Examples of therapeutic protein suitable as an immunosuppressant include, but are not limited to, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and vedolizumab.
  • Examples of monoclonal antibody suitable as an immunosupressant include, but are not limited to, basiliximab, daclizumab, and muromonab.
  • the anti-inflammatory agent suitable for use in the present method may be a cyclooxygenase (COX) inhibitor, particularly a COX-2 inhibitor, such as Celebrex, Celecoxib, Rofecoxib, Valdecoxib, DuP-697, Etoricoxib, and Lumiracoxib.
  • COX cyclooxygenase
  • the anti-infectious agent suitable for use in the present method may be an antibiotic that inhibits the growth of Gram-negative or Gram-positive bacteria.
  • antibiotic suitable for use as an anti-infectious agent include, but are not limited to, acumycin, ampicillin, amoxycillin, amphotericins, antimycins, anglomycin, avermectins, azithromycin, boromycin, carbomycins, carbapenem, ceftazidime, cethromycin, chloramphenicol, chalcomycin, ciprofloxacin, concanamycins, cirramycin, clarithromycin, colistin, cycloxacillin, daptomycin, desmethyl azithromycin, desertomycins, dihydropikromycin, dirithromycin, doxycycline, enramycin, erythromycin, flurithromycin, flumequin gentamycin, juvenimicins, kujimycins, lankamycins,
  • the amount, route of administration and dosing schedule of the present pharmaceutical composition will depend upon factors such as the specific indication to be treated, prevented, or managed, and the age, sex and condition of the patient. The roles played by such factors are well known in the art, and may be accommodated by routine experimentation.
  • the HEK293 cells were cultured in the manufacturer's suggested medium supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 units/mL penicillin, and 100 ⁇ g mL streptomycin, at 37°C in a humidified 5% C0 2 incubator.
  • FBS heat-inactivated fetal bovine serum
  • penicillin 100 units/mL penicillin
  • streptomycin 100 ⁇ g mL streptomycin
  • HEK 293 cells 2.5-5. Ox 10 4 cells/well were seeded in 96-well plate for overnight and treated with different compounds for 16-24 hours. Cell growth was determined by MTT- based colorimetric assays. Viability of the test cells treated with vehicle (0.5% DMSO) only was defined as 100% viable. Survival of cells after treatment with DETDs was calculated using the following formula:
  • Viable cell number (%) OD570 (treated cell culture)/OD57o (vehicle control) x 100.
  • TTBP HBF 4 Tri-feri-butylphosphonium tetrafluoroborate
  • NaO l Bu 289.9 mg, 3.02 mmol
  • EA ethyl acetate
  • Compound 5 was synthesized by following the process of scheme 1, using the starting material of 5-bromo-2-nitroaniline. Yield of Compound 5 was 22% (37 mg). Red solids.
  • Compound 12 was synthesized in accordance with the method set forth in Scheme 8 by use of the starting material of 2-((phenylthiol)methyl)oxirane. Yield of Compound 12 was 21% (44.7 mg).
  • Compound 1 Compound 13 was synthesized in accordance with the method set forth in Scheme 8 by use of the starting material of 4-(oxiran-2-ylmethyl)morpholine. Yield of Compound 13 was 78% (176 mg). Yellow liquid.
  • TLR4 Toll-like receptor 4
  • SEAP NF-KB-inducible secreted alkaline phosphatase
  • the TLR4-expressing cells were plated in HEK-Blue Detection (Invivogen, San Diego, Calif.) medium in a 96-well plate (25,000-50,000 cells/well). The cells were stimulated with lipopolysaccharides (LPS) alone or in combination with the compound of example 1. Cell culture without LPS and the compound of example 1 was defined as baseline control. To test whether the compound of example 1 could block that activation of the TLR4, the cells were treated with the compound of example 1 (20 ⁇ ) and LPS (final cone. 10 ng/ml/well). After a 16-24 hours incubation period at 37°C in a C0 2 incubator, The signals of individual samples in 96-well plates were detected at O.D. 6 5o nm with a Molecular Devices SpectraMax i3 Imaging Cytometer. The TLR4 activity was expressed in percentage of LPS alone-stimulated cells minus baseline control.
  • LPS lipopolysaccharides
  • the cell viability assay was performed by the MTT method. Cells were incubated with 45 ⁇ of 5 mg/ml MTT for 1 hour at 37°C, and 150 ⁇ of DMSO was added at the end of culture to dissolve the crystals. The signals of individual samples in 96-well plates were detected at O.D.570 nm with a Molecular Devices SpectraMax i3 Imaging Cytometer. Cell viability was expressed in percentage of viable LPS-stimulated cells. Results are summarized in Table 3.

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Abstract

L'invention concerne de nouveaux antagonistes du récepteur de type Toll 4 (TLR-4). Plus spécifiquement, les nouveaux antagonistes de TLR-4 sont dérivés de morphinane. L'invention concerne également l'utilisation desdits dérivés de morphinane pour traiter des maladies et/ou des troubles médiés par TLR-4, tels que des maladies auto-immunes, des maladies inflammatoires et des maladies infectieuses. L'invention concerne en outre des compositions pharmaceutiques comprenant lesdits dérivés de morphinane.
EP17889549.6A 2017-01-05 2017-12-19 Dérivés de morphinane et compositions les comprenant pour traiter des troubles auto-immuns, inflammatoires ou infectieux Withdrawn EP3565556A4 (fr)

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US7923454B2 (en) * 2002-05-17 2011-04-12 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
AU2003234621A1 (en) * 2002-05-17 2003-12-02 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20040204862A1 (en) * 2003-04-11 2004-10-14 Wainer Irving W. Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors
US7691874B2 (en) * 2004-05-14 2010-04-06 Hyoung-Chun KIM Neuroprotective properties of dextrorotatory morphinans
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CA2948144A1 (fr) * 2014-05-06 2015-11-12 Purdue Pharma L.P. Analogues du benzomorphane et leur utilisation
US9757372B2 (en) * 2015-03-25 2017-09-12 Taiwanj Pharmaceuticals Co., Ltd. Toll-like receptor 4 antagonists and use in autoimmune liver diseases
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EP3565556A4 (fr) 2020-06-10
TW201829387A (zh) 2018-08-16
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